Project Summary Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest human malignancies, and little progress towards its treatment has been achieved over the past several decades. The tumor microenvironment as a whole has been believed to be immunosuppressive. However, how different cell populations within the stroma contribute to the establishment of the immunosuppression is not fully understood. Immunotherapy has so far produced disappointing results in pancreatic cancer. A potential challenge is the redundancy of immune suppressive pathways in this disease. Thus, a thorough understanding of the biology of this disease is necessary to optimize our approaches to treatment and identify opportunities for combination therapy and prevent potential feedback mechanisms that result in tumor resistance and relapse. The research program of Unit Director Dr. Marina Pasca di Magliano's laboratory addresses the interaction between pancreatic cancer cells and components of the stroma, with the long-term goal to identify new therapeutic targets. We previously showed that ablating tumor-infiltrating myeloid cells, including tumor associated macrophages (TAMs) and myeloid derived suppressor cells, can restore anti-tumor immune response. In order to translate these results to clinically applicable strategies, we need to identify and target the signals that mediate the cross-talk between tumor cells and their microenvironment and that are responsible for immune suppression. As a research Investigator in Pasca di Magliano laboratory, I am actively pursuing two areas of research on immune regulation and fibroblasts function in pancreatic cancer. 1) I have been leading research on understanding the cross-talk between tumor cells, immune cell infiltrates and fibroblasts in the pancreatic cancer microenvironment. Within this wider project, I am focusing on identifying the signals that mediate the establishment of an immune suppressive microenvironment, in particular mechanisms involved in TAM polarization and TAM induced immune suppression, as well as investigating therapeutic modulation of the epithelial-myeloid crosstalk to improve immune checkpoint therapy in pancreatic cancer; 2) I have been contributing to project aimed at understanding fibroblast heterogeneity within pancreatic cancer, and define the origins of functions of different fibroblast subsets during the onset and progression of pancreatic cancer. My contribution also includes training of graduate and undergraduate students. I am invested in the training of junior personnel in the laboratory, and I manage collaborations with other groups. I seek to work as a team member, with primary responsibility on individual projects and a supporting role on other projects to ensure the success of Unit Director's research program.